Abstract
Purpose: Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial-mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer.Experimental design: We used transcriptomic and in situ analyses to identify PBX3 expression in colorectal cancer and cell biology approaches to determine its regulation and function. Clinical associations were analyzed in independent tissue collections and gene expression datasets of colorectal cancers with recorded follow-up data.Results: PBX3 was expressed in tumor cells with high WNT activity undergoing EMT at the leading tumor edge of colorectal cancers, whereas stromal cells were PBX3 negative. PBX3 expression was induced by WNT activation and by the EMT transcription factors SNAIL and ZEB1, whereas these effects were mediated indirectly through microRNA miR-200. PBX3 was required for a full EMT phenotype in colon cancer cells. On the protein level, PBX3 expression indicated poor cancer-specific and disease-free survival in a cohort of 244 UICC stage II colorectal cancers, and was associated with metastasis in a case-control collection consisting of 90 cases with or without distant metastasis. On the mRNA level, high PBX3 expression was strongly linked to poor disease-free survival.Conclusions: PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer. Clin Cancer Res; 24(8); 1974-86. ©2018 AACR.
Highlights
Colorectal cancer ranks third in cancer incidence among men and women and is a major cause of cancer morbidity and mortality [1]
Pre–B-cell leukemia homeobox transcription factor 3 (PBX3) was expressed in tumor cells with high WNT activity undergoing epithelial–mesenchymal transition (EMT) at the leading tumor edge of colorectal cancers, whereas stromal cells were PBX3 negative
PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer
Summary
Colorectal cancer ranks third in cancer incidence among men and women and is a major cause of cancer morbidity and mortality [1]. More than 80% of colorectal cancers have driver mutations in APC or b-catenin that over activate WNT signaling in these tumors [2]. These mutations are present in all clonally derived colon cancer cells, WNT signaling still remains regulated in these tumors, which is reflected by coexistence of tumor cell subpopulations with relatively low or high WNT activity [3]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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